The sexually transmitted disease gonorrhea, caused by Neisseria gonorrhoeae, continues to be a significant source of morbidity in the United States and around the world. Not only does it disproportionately affect certain minority populations (Black, non-Hispanic), but infects at rates >200 per 100,00 in five of the southeastern states. There remains no vaccine and the antibiotics that have been successfully used to treat this disease over the years have become ineffective one after another The CDC recommended treatment for gonococcal infections is now limited to a single class of drug, cephalosporins. The long-term goal of this project is to provide novel means to prevent this infection through interfering with the ability of a pilus accessory protein designated PilC, to interact with human cells. Because the PilC acts early in the infectious process we posit that interfering with its action could avert all the downstream steps of infection, thereby preventing infection. To accomplish this interference we need to better understand what parts of this large protein are involved in the act of adherence to human cells. To that end we will develop specific antibodies, mutations, and peptides that interfere with PilC-mediated adherence. We will develop a three-dimensional structural understanding of PilC that will guide our efforts to interfere with its adherence functions. We will establish PilC critical role in initiating infections using the experimental human infection model and investigate the significance gonococci maintaining two independent copies of the pilC gene.